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The effect of glycine on 1-methyl-4-phenylpyridinium ion (MPP + )-induced hydroxyl radical (OH) formation in the extracellular fluid of rat striatum were investigated. Rats were anesthetized and sodium salicylate in Ringer's solution (0.5 nmol/μl/min) was infused through a microdialysis probe to detect the generation of OH as reflected by the non-enzymatic formation of 2,3-dihydroxybenzoic acid (2,3-DHBA) in rat striatum. MPP + (5 mmol/L) produced an increase in OH formation. When glycine (1 mmol/L) was infused into the rat striatum through a microdialysis probe after MPP + treatment, the marked in the level of 2,3-DHBA was observed in the brain dialysate. However, in the presence of MK-801 (100 μmol/L), a non competitive antagonist of N-methyl-D-aspartate (NMDA), glycine failed to increase the 2,3-DHBA formation by MPP + . When corresponding experiments were performed with nitro-L arginine (L-NNA) (1 mmol/L), a nitric oxide synthase (NOS) inhibitor, same result was obtained. These results suggest that MPP + -induced OH generation may modulated by glycine via NMDA receptor in rat striatum. This increase might be explained because of the presence of a glutaminergic tonic action., (Copyright © 2019. Published by Elsevier B.V.)

The present study examined whether tamoxifen could suppress antidepressant drug phenelzine can increase an active dopaminergic neurotoxin, 1-methyl-4-phenylpyridinium ion (MPP+)-induced hydroxyl radical (*OH) generation in the extracellular fluid of rat striatum, using in vivo microdialysis system. Rats were anesthetized, and sodium salicylate (0.5 nmol/microl/min) was infused through a microdialysis probe to detect the generation of *OH as reflected by the non-enzymatic formation of 2,3-dihydroxybenzoic acid (DHBA) in the striatum. Infusion of phenelzine (0.1 mM or 0.1 nmol/microl/min) into the striatum drastically increased dopamine (DA) efflux and the *OH formation, trapped as 2,3-DHBA by the possible increased production of MPP+. However, tamoxifen (100 microM) significantly suppressed phenelzine enhanced DA efflux and *OH formation by MPP+. These results in the pressent study is the first demonstration showing the protective effect of tamoxifen on *OH generation induced by phenelzine enhanced MPP+ by suppressing DA efflux.

The present study examined whether tamoxifen could suppress antidepressant drug phenelzine can increase an active dopaminergic neurotoxin, 1-methyl-4-phenylpyridinium ion (MPP+)-induced hydroxyl radical (*OH) generation in the extracellular fluid of rat striatum, using in vivo microdialysis system. Rats were anesthetized, and sodium salicylate (0.5 nmol/microl/min) was infused through a microdialysis probe to detect the generation of *OH as reflected by the non-enzymatic formation of 2,3-dihydroxybenzoic acid (DHBA) in the striatum. Infusion of phenelzine (0.1 mM or 0.1 nmol/microl/min) into the striatum drastically increased dopamine (DA) efflux and the *OH formation, trapped as 2,3-DHBA by the possible increased production of MPP+. However, tamoxifen (100 microM) significantly suppressed phenelzine enhanced DA efflux and *OH formation by MPP+. These results in the pressent study is the first demonstration showing the protective effect of tamoxifen on *OH generation induced by phenelzine enhanced MPP+ by suppressing DA efflux.

Although neuroprotective effect of nitric oxide (NO) is discussed, NO has a role of pathogenesis of cellular injury. NO is synthesized from L-arginine by NO synthase (NOS). NO contributes to the extracellular potassium-ion concentration ([K(+)](o))-induced hydroxyl radical ((*)OH) generation. Cytotoxic free radicals such as peroxinitrite (ONOO(-)) and (*)OH may also be implicated in NO-mediated cell injury. NO activation was induced by K(+) depolarization. NO may react with superoxide anion (O(2) (-)) to form ONOO(-) and its decomposition generates (*)OH. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) metabolite 1-methyl-4-phenylpyridinium ion (MPP(+)) involve toxicity induced by NO. Intraneuronal Ca(2+) triggered by MPP(+) may be detrimental to the functioning of dopaminergic nerve terminals in the striatum. Although the [K(+)](o)-induced depolarization enhances the formation of (*)OH product due to MPP(+), the (*)OH generation via NOS activation may be unrelated the dopamine (DA)-induced (*)OH generation. Depolarization enhances the MPP(+)-induced (*)OH formation via NOS activation. NOS inhibition is associated with a protective effect due to suppression of depolarization-induced (*)OH generation. ONOO(-) has been implicated as a causative factor under conditions in which DA neurons are damaged. These findings may be useful in elucidating the actual mechanism of free radical formation in the pathogenesis of neurodegenerative brain disorders, including Parkinson's disease and traumatic brain injuries.

The present study examined whether or not immobilization stress (IMMO)-inducible semicarbazide-sensitive amine oxidase (SSAO) inhibitor by separated gel filtration from 105,000 g supernate in rat brain cytosol contribute to the dopamine (DA) efflux by 1-methyl-4-phenylpyridinium ion (MPP(+)) in the rat striatum. The isoelectric point (pI) value of this inhibitor was determined by isoelectric focusing (IEF)-gel electrophoresis to about 3.8. The application of IMMO-induced SSAO inhibitor (3 microg) by IEF-gel electrophoresis increased DA efflux by MPP(+) in rat striatum. These results suggest that IMMO-inducible endogenous SSAO inhibitor enhances DA efflux by MPP(+).

The present study was examined that the desferrioxamine, a strong iron (III) chelator, enhanced 1 methyl-4-phenylpyridinium ion (MPP+)-induced hydroxyl radical (*OH) generation in the extracellular fluid of caudate nucleus anesthetized rats. Rats were anesthetized, and sodium salicylate in Ringer's solution (0.5 nmol/microl/min) was infused through a microdialysis probe to detect the generation of *OH as reflected by the non-enzymatic formation of 2,3-dihydroxybenzoic acid (DHBA) in the striatum. Induction of desferrioxamine (50 microM) drastically increased the formation of *OH trapped as 2,3-DHBA by the action of MPP+, as compared with MPP+-only-treated animals. Although desferrioxamine did not change the levels of MPP+-induced dopamine, a marked elevation of *OH formation trapped as 2,3-DHBA was observed. When corresponding experiments were performed with reserpinized animals, the level of dopamine and 2,3-DHBA drastically decreased. However, the level of dopamine did not change, but desferrioxamine significantly increased the level of 2,3-DHBA in reserpinized animals. Iron (III) decreased MPP+-induced 2,3-DHBA formations in the presence of dopamine (10 microM). Moreover, when iron (II) was administered to desferrioxamine-treated animals, a marked elevation of 2,3-DHBA was observed, compared with MPP+-only-treated animals, that showed a positive linear correlation between iron (II) and *OH formation trapped as 2,3-DHBA (R2=0.981) in the dialysate. The present study indicates that the suppression of MPP+-induced *OH formation by iron (III) may play a key role in protective effect of iron (III) on the rat brain.

The present study was examined whether diltiazem, a L-type Ca2+ channel antagonist, could suppresses 1 methyl-4-phenylpyridinium ion (MPP+)-induced dopamine (DA) in extracellular fluid of rat striatum. Ouabain (100 microM; 100 microM or 100 pmol/microl per min) significantly enhanced the level of DA by MPP+. However, in the presence of diltiazem (100 microM) significantly suppressed the level of DA release by ouabain and MPP+. These results suggest that diltiazem suppresses Ca2+ -dependent release of DA by ouabain-induced Ca2+ overload.

The present study was examined whether tamoxifen, a synthetic nonsteroidal antiestrogen, could suppress antidepressant drug phenelzine can increase an active dopaminergic neurotoxin, 1-methyl-4-phenylpyridinium ion (MPP(+))-induced hydroxyl radical (OH) generation in the extracellular fluid of rat striatum, using in vivo microdialysis system. Rats were anesthetized, and sodium salicylate (0.5 nmol/microl/min) was infused through a microdialysis probe to detect the generation of OH as reflected by the non-enzymatic formation of 2,3-dihydroxybenzoic acid (DHBA) in the striatum. Infusion of phenelzine (100 microM or 0.1 nmol/microl/min) into the striatum drastically increased dopamine (DA) efflux and the OH formation, trapped as 2,3-DHBA by the possible increased production of MPP(+). However, tamoxifen (100 microM) significantly suppressed phenelzine enhanced DA efflux and OH formation by MPP(+). These results in the present study is the first demonstration showing the protective effect of tamoxifen on OH generation induced by phenelzine enhanced MPP(+) by suppressing DA efflux.

The present study examined the effect of chelerlythrine, a protein kinase C (PKC) inhibitor, on 1-methyl-4-phenylpyridine (MPP+)-induced hydroxyl radicals (*OH) in rat striatum. Rats were anesthetized, and sodium salicylate (0.5 mM or 0.5 nmol/microl/min) was infused through a microdialysis probe to detect the *OH generation as reflected by the non-enzymatic formation of 2,3-dihydroxybenzoic acid (2,3-DHBA) in the striatum. Dopamine (DA)-selective neurotoxin, MPP+, infusion into the striatum of rats induces *OH formation, trapped as 2,3-DHBA. The application of chelerythrine, a potent and selective protein kinase C (PKC) inhibitor, suppressed MPP+ -induced *OH formation. The results in the present study suggests the protective effect of chelerythrine on *OH generation induced by MPP+.

The present study examined the antioxidant effects of angiotensin-converting enzyme inhibitor (ACE), imidaprilat, on para-nonylphenol and 1-methyl-4-phenylpyridinium ion (MPP+)-induced hydroxyl radical (*OH) formation and dopamine (DA) efflux in extracellular fluid of rat striatum, using a microdialysis technique. para-Nonylphenol clearly enhanced *OH formation and DA efflux induced by MPP+. When imidaprilat was infused in para-nonylphenol and MPP+-treated rats, DA efflux and *OH formation significantly decreased, as compared with that in the para-nonylphenol and MPP+-treated control. Imidaprilat was able to scavenge *OH and DA efflux induced by para-nonylphenol and MPP+. When iron(II) was administered to para-nonylphenol-pretreated animals, iron(II) clearly produced a dose-dependent increase in the levels of 2,3-dihydroxybenzoic acid (2,3-DHBA), as compared with MPP+-only-treated rats. A positive linear correlation was observed between iron(II) and 2,3-DHBA (R2=0.985) in the dialysate. However, in the presence of imidaprilat, a small increase in the levels of 2,3-DHBA products was observed. The results suggest that imidaprilat may protect against para-nonylphenol and MPP+-induced *OH formation via suppressing DA efflux in the rat striatum.

The present study examined the ability of antioxidant effects of angiotensin-converting enzyme (ACE) inhibitor, imidaprilat, on the synergistic effect of bisphenol A and 1-methyl-4-phenylpyridinium ion (MPP(+))-induced hydroxyl radical (*OH) formation and dopamine (DA) efflux in extracellular fluid of rat striatum. Bisphenol A clearly enhanced OH formation and DA efflux induced by MPP(+). When imidaprilat was infused in bisphenol A and MPP(+)-treated rats, DA efflux and OH formation significantly decreased, as compared with that in the bisphenol A and MPP(+) treated control. These results suggest that ACE inhibitors may protect against the synergistic effect of bisphenol A and MPP(+)-induced OH formation via suppressing DA efflux in the rat striatum.

The present study was examined whether or not 2-bromoethyamine, a semicarbazide-sensitive amine oxidase (SSAO, EC; 1.4.3.6) inhibitor, would increase an active dopaminergic neurotoxin, 1-methyl-4-phenylpyridinium ion (MPP(+))-induced hydroxyl radical ((*)OH) generation in the rat striatum. Rats were anesthetized, and sodium salicylate (0.5 mM or 0.5 nmol/microl/min) was infused through a microdialysis probe to detect the generation of (*)OH as reflected by the non-enzymatic formation of 2,3-dihydroxybenzoic acid (DHBA) in the striatum. Infusion of 2-bromoethylamine (100 microM or 100 pmol/microl/min) into the striatum drastically increased the formation of (*)OH products, trapped as DHBA by the action of MPP(+). Further, I studied the effect of allopurinol, a xanthine oxidase inhibitor, an 2-bromoethylamine and MPP(+)-induced (*)OH generation. Allopurinol (10 microM or 10 pmol/microl/min) significantly suppressed 2-bromoethyamine and MPP(+)-induced (*)OH. These results suggest that a definite mechanism is not clear at the moment, after inhibition of tissue-bound and/or blood plasma SSAO activity, with consequent increases in bioactive amine levels, enhances the formation of (*)OH products of efflux/oxidation due to MPP(+).

The present study examined the antioxidant effect of phytic acid on iron (II)-enhanced hydroxyl radical (*OH) generation induced by 1-methyl-4-phenylpyridinium ion (MPP(+)) in the extracellular fluid of rat striatum. Rats were anesthetized, and sodium salicylate in Ringer's solution (0.5 nmol/microl/min) was infused through a microdialysis probe to detect the generation of *OH as reflected by the non-enzymatic formation of 2,3-dihydroxybenzoic acid (DHBA) in the striatum. Phytic acid (100 microM) did not significantly decrease the levels of MPP(+)-induced *OH formation trapped as 2,3-DHBA. To confirm the generation of *OH by the Fenton-type reaction, iron (II) was infused through a microdialysis probe. Introduction of iron (II) (10 microM) enhanced MPP(+) induced *OH generation. However, phytic acid significantly suppressed iron (II)-enhanced *OH formation after MPP(+) treatment (n=6, P<0.05). These results suggest that the antiradical effect of phytic acid occurs by chelating iron required for the MPP(+)-enhanced *OH generation via the Fenton-type reaction.

We examined whether ouabain-induced Ca(2+) overload increases hydroxyl radical (*OH) generation by 1-methyl-4-phenylpyridinium ion (MPP(+)) in rat striatum. These elevations seem to induce lipid peroxidation of striatum of rats, as detected by increases in non-enzymatic formation of 2,3-dihydroxybenzoic acid (DHBA) levels. Ouabain enhanced MPP(+)-induced *OH formation trapped as DHBA. Moreover, when iron (II) was administered to MPP(+) then ouabain (100 micro M)-pretreated animals, a marked elevation in the level of DHBA was observed, as compared with the iron (II)-only-treated animals. These results suggests that Ca(2+) overload might enhance *OH generation by MPP(+) in rat striatum.

The present study examined whether bisphenol A enhanced 1-methyl-4-phenylpyridinium ion (MPP+)-induced hydroxyl radical (*OH) generation in rat striatum using microdialysis technique. These elevations were detected by increases in non-enzymatic formation of 2,3-dihydroxybenzoic acid levels. Bisphenol A significantly enhanced MPP+-induced.OH generation. Further, the effect of diltiazem, a L-type Ca2+ channel antagonist, on bisphenol A (10 microM) and MPP+ (5 mM)-induced.OH generation were studied. Ddiltiazem (100 microM) significantly suppressed bisphenol A and MPP+-induced.OH generation. The results indicate bisphenol A augmented *OH generation, and diltiazem may have preventive effect on bisphenol A and MPP+-induced.OH generation.

The present study examined the ability of antioxidant effects of nicotine on 1-methyl-4-phenylpyridinium ion (MPP(+))-induced hydroxyl radical (*OH) formation of rat striatum. Rats were anesthetized and sodium salicylate in Ringer's solution (0.5 nmol/microl per min) was infused through a microdialysis probe to detect the generation of.OH as reflected by non-enzymatic formation trapped as 2,3-dihydroxybenzoic acid (DHBA) in the striatum. MPP(+) enhanced generation of.OH formation trapped as DHBA. However, nicotine (100 microM) significantly suppressed.OH formation induced by MPP(+). Iron (II) (2, 5 and 10 microM) increased the levels of DHBA in a concentration-dependent manner. However, in the presence of nicotine (100 microM), the effect of nicotine was suppressed. These results suggest that nicotine has a preventive effect on.OH generation by MPP(+) in rat striatum.

Reactive oxygen species have been implicated in dopaminergic toxicity caused by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and iron. Although MPTP produces a parkinsonian syndrome after its conversion to 1-methyl-4-phenylpyridine (MPP(+)) by type B monoamine oxidase (MAO-B) in the brain, the etiology of this disease remains obscure. MPP(+) is a highly potent dopaminbergic-releasing agents and dopamine (DA) autoxidation catalyzed by iron and oxidative stress may be involved in the pathogenesis of Parkinson's disease. Neuromelanine synthesis from DA produce highly reactive free radicals. Although the controversy possible neurotoxin and/or neuroprotective roles of nitric oxide (NO) was discussed, NO contributes to oxidative injury to brain neurons in vivo. An environmental estrogen-like chemical also related to MPP(+)-induced *OH generation. This review describes actual mechanism of the free radicals formation by dialysis studies of in vivo free radical trapping in the pathogenesis of neurodegenerative disorders, including in the Parkinson's disease, Alzheimer disease and traumatic brain injuries.

The present study examined the antioxidant effect of histidine, a singlet oxygen ((1)O(2)) scavenger, on para-nonylphenol (an environmental estrogen-like chemical)-enhanced hydroxyl radical (.OH) generation induced by 1-methyl-4-phenylpyridinium ion (MPP+) in extracellular fluid of rat striatum. Rats were anesthetized, and sodium salicylate in Ringer's solution (0.5 nmol/microl/min) was infused through a microdialysis probe to detect the generation of.OH as reflected by the non-enzymatic formation of 2,3-dihydroxybenzoic acid (DHBA) in the striatum. Introduction of para-nonylphenol (10 microM) significantly enhanced MPP+ -induced.OH generation. Histidine (25 mM) decreased the para-nonylphenol-enhanced.OH formation. Although the level of MPP+ -induced.OH formation trapped as DHBA after para-nonylphenol treatment increased, para-nonylphenol failed to increase either the level of dopamine and DHBA formation in the reserpinized animals. These results indicate that para-nonylphenol and MPP+ -enhanced.OH generation was based on 1O(2) production, and histidine may have a preventive effect on para-nonylphenol and MPP+ -induced.OH generation in rat striatum.

We examined whether tamoxifen could suppress 1-methyl-4-phenylpyridine (MPP(+))-induced hydroxyl radical generation in the extracellular fluid of rat striatum, using in vivo microdialysis system. MPP(+) (5 mM) enhanced generation of hydroxyl radicals with concomitant increased efflux of dopamine. Tamoxifen (1--100 microM) dose-dependently suppressed the hydroxyl radical formation induced by MPP(+). Tamoxifen (100 microM) significantly attenuated dopamine efflux induced by MPP(+). The result in the present study is the first demonstration showing the protective effect of tamoxifen on hydroxyl radical generation induced by MPP(+) by suppressing dopamine efflux.

In Parkinson's disease (PD), the dopamine (DA) neuronal cell death in the nigrostriatal system has been proposed to be mediated by reactive oxygen radicals such as hydroxyl radicals (.OH). This.OH production may cause lipid peroxidation of cell membranes leading to neuronal cell death. This paper report that the DA-selective neurotoxin, 1-methyl-4-phenylpyridinium ion (MPP(+)), (1 nmol/microl per min for 1 h) infusion into the striatum of rats induces elevation of extracellular DA and.OH formation. These elevations seem to induce lipid peroxidation of striatum membranes, as detected by increases in non-enzymatic formation of 2,3-dihydroxybenzoic acid (DHBA) levels. To test the involvement of DA release in the.OH generation and lipid peroxidation, the rats were pretreated with reserpine (5 mg/kg, i.v., 24 h before MPP(+) or without MPP(+)) to deplete presynaptic DA. Reserpine treatment alone did not change the levels of DA or 2,3-DHBA, while the combined treatment with both MPP(+) and reserpine clearly decreased 2,3-DHBA, as well as DA levels, compared to those in the group treated with MPP(+) alone. After injection into reserpinized rats, DA at various doses (2, 5 and 10 microM) small increased 2,3-DHBA levels dose-dependently, as compared to the MPP(+) alone-treated group. These results clearly indicate that MPP(+) perfusion into the striatum increases extracellular DA levels and this increase may concomitantly induce the formation of reactive free oxygen radicals, such as.OH free radicals. These events may contribute, at least in part, to the nigrostriatal neurons cell death after MPP(+).

We recently demonstrated that para-nonylphenol, an environmental estrogen-like chemical, enhances hydroxyl radical (*OH) generation in the rat striatum. In the present study we have examined whether para-nonylphenol enhanced 1-methyl-4-phenylpyridinium ion (MPP(+))-induced *OH generation in the rat striatum using a microdialysis technique. Para-nonylphenol significantly enhanced MPP(+)-induced *OH generation. Further, we studied the effect of allopurinol, a xanthine oxidase inhibitor, on para-nonylphenol and MPP(+)-induced *OH generation. Allopurinol significantly suppressed para-nonylphenol and MPP(+)-induced *OH generation. The results indicate that para-nonylphenol enhanced *OH generation based on superoxide anion production, and allopurinol may have preventive effect on para-nonylphenol and MPP(+)-induced *OH generation.

We examined the effect of N(G)-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase (NOS) inhibitor, on extracellular potassium ion concentration ([K(+)](o))-enhanced hydroxyl radical (.OH) generation due to 1-methyl-4-phenylpyridinium ion (MPP(+)) was examined in the rat striatum. Rats were anesthetized, and sodium salicylate in Ringer's solution (0.5 nmol/microl per min) was infused through a microdialysis probe to detect the generation of.OH as reflected by the non-enzymatic formation of 2,3-dihydroxybenzoic acid (DHBA) in the striatum. Induction of KCl (20, 70 and 140 mM) increased MPP(+)-induced.OH formation trapped as 2,3-dihydroxybenzoic acid (DHBA) in a concentration dependent manner. However, the application of L-NAME (5 mg/kg i.v.) abolished the [K(+)](o) depolarization-induced.OH formation with MPP(+). Dopamine (DA; 10 microM) also increased the levels of DHBA due to MPP(+). However, the effect of DA after application of L-NAME did not change the levels of DHBA. On the other hand, the application of allopurinol (20 mg/kg i.v., 30 min prior to study), a xanthine oxidase (XO) inhibitor was abolished the both [K(+)](o)- and DA-induced.OH generation. Moreover, when iron(II) was administered to MPP(+) then [K(+)](o) (70 mM)-pretreated animals, a marked increase in the level of DHBA. However, when corresponding experiments were performed with L-NAME-pretreated animals, the same results were obtained. Therefore, NOS activation may be no relation to Fenton-type reaction via [K(+)](o) depolarization-induced.OH generation. The present results suggest that [K(+)](o)-induced depolarization augmented MPP(+)-induced.OH formation by enhancing NO synthesis.

The present study examined the antioxidant effect of histidine on extracellular potassium ion concentration, [K+]o-induced depolarization enhances 1-methyl-4-phenylpyridinium ion (MPP+)-induced hydroxyl radical (*OH) generation in the rat striatum. Rats were anesthetized and sodium salicylate in Ringer's solution (0.5 nmol/M microl/min) was infused through a microdialysis probe to detect the generation of *OH as reflected by the nonenzymatic formation of 2,3-dihydroxybenzoic acid (DHBA) in the striatum. Induction of [K+]o (20, 70 and 140 mM) significantly increased the level of 2,3-DHBA by the action of MPP+ (5 mM) in a concentration-dependent manner. However, histidine (25 mM) reduced the [K+]o-induced *OH formation. Although the level of MPP+-induced dopamine (DA) and 2,3-DHBA formation after [K+]o (70 mM) treatment increased, [K+]o failed to increase either the level of MPP+-induced DA and 2,3-DHBA in the reserpinized group. When iron (II) was administered to [K+]o (70 mM)-pretreated rats, iron (II) clearly produced a dose-dependent increase in the level of 2,3-DHBA, as compared with MPP+-only treated rats. However, in the presence of histidine (25 mM), the effect of [K+]o was abolished. These results indicated that histidine may reduce the [K+]o-induced depolarization enhanced *OH formation by the action of MPP+ in the rat striatum.

We determined the methamphetamine (MA), a potent dopamine (DA) releaser, enhances 1-methyl-4-phenylpyridinium ion (MPP(+))-induced hydroxyl radical (&z.rad;OH) generation in the rat striatum. Rats were anesthetized, and sodium salicylate in Ringer's solution (0.5 nmol/microl/min) was infused through a microdialysis probe to detect the generation of .OH as reflected by the non-enzymatic formation of 2,3-dihydroxybenzoic acid (DHBA) in the striatum. After administration of MA (5 mg/kg i.v., every 2 h, four times), MA drastically increased DA release and the &z.rad;OH formation. When iron (II) was administered to the MA-treated animals, a marked elevation of DHBA was observed, compared with MPP(+)-only treated animals, that showed a positive linear correlation between DA and .OH formation trapped as DHBA (R(2)=0.985) in the dialysate. These results suggest that MA enhances the &z.rad;OH products of efflux/oxidation due to MPP(+).

We examined whether fluvastatin, an inhibitor of low-density lipoprotein (LDL) oxidation, can resist 1-methyl-4-phenylpyridine (MPP(+))-induced hydroxyl radical generation (.OH) in the extracellular fluid of rat striatum. Rats were anesthetized and sodium salicylate in Ringer's solution (0.5 nmol/microliter/min) was infused through a microdialysis probe to detect the generation of.OH as reflected by the nonenzymatic formation of 2,3-dihydroxybenzoic acid (DHBA) in the striatum. MPP(+) (5 mM; total dose 75 nmol) clearly produced an increase in.OH formation. However, fluvastatin (100 microM) reduced the.OH formation by the action of MPP(+). These results indicated that fluvastatin, a potent inhibitor of LDL oxidation, may resist the formation of.OH products of MPP(+).

We determined that extracellular potassium ion concentration, [K+]o-induced depolarization, enhances 1-methyl-4-phenylpyridinium ion (MPP+)-induced hydroxyl radical (*OH) generation in the rat striatum. Rats were anesthetized, and sodium salicylate in Ringer's solution (0.5 nmol/microl/min) was infused through a microdialysis probe to detect the generation of *OH as reflected by the non-enzymatic formation of 2,3-dihydroxybenzoic acid (DHBA) in the striatum. Induction of high concentration KCl (70 mM) drastically increased formation of *OH trapped as DHBA by the action of MPP+. When dopamine (DA) was administered to the high KCl-treated animals, a marked elevation of DHBA was observed, compared with MPP+-only-treated animals, that showed a positive linear correlation between DA and *OH formation trapped as DHBA (R2 = 0.979) in the dialysate. When corresponding experiments were performed with iron (II), the same results were obtained: a positive linear correlation between the release of iron (II) and DHBA (R2 = 0.988) in the dialysate. These results suggest that [K+]o-induced depolarization enhances the formation of *OH products of efflux/oxidation due to MPP+.

We examined the antioxidant effects of angiotensin-converting enzyme inhibitor on 1-methyl-4-phenylpyridinium ion (MPP+)-induced hydroxyl radical (*OH) formation in extracellular fluid of rat striatum. Rats were anesthetized and sodium salicylate in Ringer's solution (0.5 nmol microl(-1) min(-1) was infused through a microdialysis probe to detect the generation of *OH, as reflected by the non-enzymatic formation of 2,3-dihydroxybenzoic acid (DHBA) in the striatum. MPP+ clearly produced an increase in *OH formation in a concentration-dependent manner. When imidaprilat was infused in MPP+ -pre-treated animals, the formation of dopamine and 2,3-DHBA significantly decreased, as compared with that in the MPP+ -only-treated group. We compared the ability of two non-SH-containing angiotensin-converting enzyme inhibitors (imidaprilat and enalaprilat) with an SH-containing angiotensin-converting enzyme inhibitor (captopril) to scavenge *OH. All three angiotensin-converting enzyme inhibitors were able to scavenge *OH generated by the action of MPP+. However, the changes produced by captopril and enalaprilat were not significant. When dopamine was administered to the MPP+ -pre-treatment group, a marked elevation was observed, showing a positive linear correlation between dopamine and *OH formation (2,3-DHBA) in the dialysate. Moreover, when iron (II) was administered to the MPP+ -pre-treatment group, the same results were obtained: a positive linear correlation (R2 = 0.989) between the release of dopamine and 2,3-DHBA (R2 = 0.989) in the dialysate. When corresponding experiments were performed with imidaprilat-pre-treated animals, the level of 2,3-DHBA decreased. These results suggested that angiotensin-converting enzyme inhibitors may protect against MPP+ -induced *OH formation in the rat striatum.

The present study investigated the blockage of dopamine (DA) oxidation by reserpine. 1-Methyl-4 phenylpyridinium ion (MPP+) increased the release of DA and the formation of hydroxyl radical ( r22. OH). The r22. OH generated by DA when captured as the hydroxylated derivative of salicylic acid was measured by the high-performance liquid chromatographic-electrochemical (HPLC-EC) procedure. MPP+ concentration for half-maximal effect of DA producing release (EC50) was 5.2 mM. The maximum attainable concentration of dialysate DA (Emax) by MPP+ was 7.7 microM. However, the EC50 and Emax values with reserpinized animal were 5.2 mM and 1.2 microM, respectively. When high concentration of pargyline (10 mM) were infused in MPP+ (5 mM)-pretreated animals, a marked elevation of DA and r22. OH formation was observed. The level of DA and 2, 3-DHBA formations was drastically reduced, as compared with the MPP+-only treated group. Although the levels of MPP+-induced DA and 2,3-DHBA formation after pargyline treatment increased, pargyline failed to increase either the level of MPP+-induced DA or 2,3-DHBA in the reserpinized group. When DA was administered to the MPP+-pretreatment group, a marked elevation was observed, showing a positive linear correlation DA and r22. OH formation trapped as 2,3-DHBA (R2=0.978) in the dialysate. When corresponding experiment were performed with iron (II), the same results were obtained: a positive linear correlation between the release of DA and 2,3-DHBA (R2=0.989) in the dialysate. These results indicated that reserpine-induced DA depletion may reduce MPP+-induced r22. OH formation., (Copyright 1999 Elsevier Science B.V.)

We investigated the efficacy of histidine on MPP+-induced hydroxyl radical (.OH) formation in extracellular fluid of rat striatum. Rats were anesthetized and sodium salicylate in Ringer's solution (0.5 nmol microl-1 min-1) was infused through a microdialysis probe to detect the generation of.OH as reflected by the nonenzymatic formation of 2,3-dihydroxybenzoic acid (DHBA) in the striatum. MPP+ (5 mM) clearly produced an increase in.OH formation. However, histidine (25 mM) reduced the.OH formation by the action of MPP+. These results indicate that histidine protects MPP+-induced.OH formation in rat striatum., (Copyright 1999 Elsevier Science B.V.)

Ringer's solution containing salicylic acid (5 nmol/microliters/min) was infused directly through an intracranial microdialysis probe to detect the generation of hydroxyl radicals (.OH) reflected by the formation of dihydroxybenzoic acids (DHBA) in the caudate nucleus of anesthetized rats. Brain dialysate was assayed for dopamine, 2,3-, and 2,5-DHBA by a high-pressure liquid chromatography-electrochemical (HPLC-EC) procedure. 1-Methyl-4-phenylpyridinium ions (MPP+, 0 to 150 nmol) increased dose-dependently the release of dopamine and the formation of DHBA. A positive linear correlation between the release of dopamine and the formation of 2,3- or 2,5-DHBA was observed (R2 = .98). The present results demonstrate the validity of the use of not only 2,3-DHBA but also 2,5-DHBA as an in vivo index of oxidative damage generated by reactive .OH radicals. In conclusion, the present study demonstrates a novel use of intracranial microdialysis of salicylic acid to assess the oxidative damage elicited by .OH in living brain.